De novo assembly and annotation of the North American bison (Bison bison) reference genome and subsequent variant identification.

Genomic tools have improved the ability to manage bison populations and enhanced efforts to conserve this iconic species. These tools have been particularly useful for detecting introgression of cattle genome within bison herds but are limited by the need to use the cattle genome as a surrogate for mapping reads. This complicates efforts to distinguish the species of origin of chromosomal segments in individual bison at the genomic level. An assembly (Bison_UMD1.0) based on 75X genome coverage by Illumina and 454 reads was generated using the MaSuRCA assembler, generating a 2.81 Gigbases de novo reference genome from American bison. Comparison of bison and domestic cattle references identified 28 443 364 single nucleotide variants and 2 627 645 insertions/deletions distinguishing the species. Sequence alignment of an additional 12 modern bison samples and two historic bison samples to domestic cattle and bison references provides a dataset of genomic variants defining the different species and within-species variation. This first annotated draft assembly represents a resource for the management and conservation of bison, as well as a means to study the effects on the genome of interspecies hybridization. The comparisons of historical bison sequences with the new bison reference identified genomic differences between modern and pre-population bottleneck bison. The results support the application of genomics to enhance future research on disease, the establishment of satellite conservation herds and insight into bison and cattle speciation. The first genome assembly for bison and dataset provides a foundation that can be built upon as genetic technologies improve over the years.

The outcomes of health-promoting communities: being active eating well initiative-a community-based obesity prevention intervention in Victoria, Australia.

OBJECTIVE: The aim of this study is to evaluate the impact of the Health-Promoting Communities: Being Active Eating Well (HPC:BAEW, 2007-2010) initiative, which comprised community-based multi-component interventions adapted to community context in five separate communities. The intervention aimed to promote healthy eating, physical activity and stronger, healthier communities. METHODS: A mixed method and multilevel quasi-experimental evaluation of the HPC:BAEW initiative captured process, impact and outcome data. The evaluation involved both cross-sectional (children and adolescents) and longitudinal designs (adults) with data collected pre- and post-intervention in intervention (n=2408 children and adolescents from 18 schools, n=501 adults from 22 workplaces) and comparison groups (n=3163 children and adolescents from 33 schools, n=318 adults from seven workplaces). Anthropometry, obesity-related behavioural and environmental data, information regarding community context and implementation factors were collected. The primary outcomes were differences in anthropometry (weight, waist, body mass index (BMI) and standardised BMI (BMI z-score)) over time compared with comparison communities. Baseline data was collected 2008/2009 and post-intervention collected in 2010 with an average intervention time frame of approximately 12 months. RESULTS: The strategies most commonly implemented were related to social marketing, stakeholder engagement, network and partnership development, community-directed needs assessment and capacity building. Analysis of post-intervention data showed gains in community capacity, but few impacts on environments, policy or individual knowledge, skills, beliefs and perceptions. Relative to the comparison group, one community achieved a lower prevalence of overweight/obesity, lower weight, waist circumference and BMI (P<0.005). One community achieved a higher level of healthy eating policy implementation in schools; two communities achieved improved healthy eating-related behaviours (P<0.03); one community achieved lower sedentary behaviours; and one community achieved higher levels of physical activity in schools (P<0.05). All effect sizes were in the small-to-moderate range. CONCLUSIONS: This was a complex and ambitious initiative, which attempted to expand a previously successful community-based intervention in Victoria into five new contexts and communities. Overall, project success was quite inconsistent, and some significant differences were in the unanticipated direction. However, there are many important learnings that should inform future health-promotion activities. The heterogeneity of outcomes of HPC:BAEW communities reflects the reality of life whereby effectiveness of intervention strategies is dependent on individual and community factors. Future health promotion should consider a systems approach whereby existing systems are modified rather than relying heavily on the addition of new activities, with longer time frames for implementation.

Concizumab, an anti-tissue factor pathway inhibitor antibody, induces increased thrombin generation in plasma from haemophilia patients and healthy subjects measured by the thrombin generation assay.

AIMS: Concizumab, a humanized monoclonal antibody against tissue factor pathway inhibitor (TFPI), is being developed as a subcutaneously (s.c.) administered treatment for haemophilia. It demonstrated a concentration-dependent procoagulant effect in functional TFPI assays; however, global haemostatic assays, such as the thrombin generation assay (TGA), offer a more complete picture of coagulation. We investigated how concizumab affects thrombin generation following ex vivo spiking in plasma from haemophilia patients using the TGA, and if the assay can detect the effect of multiple s.c. concizumab doses in healthy subjects. METHODS: For the ex vivo spiking study, platelet-poor plasma (PPP) from 18 patients with severe haemophilia was spiked with 0.001-500 nm concizumab. For the multiple-dosing study, four healthy males received concizumab 250 µg kg-1 s.c. every other day for eight doses; blood was collected before and after dosing and processed into PPP. In both studies, thrombin generation was measured using a Calibrated Automated Thrombogram® system with 1 pm tissue factor. RESULTS: In spiked samples from haemophilia patients, peak thrombin and endogenous thrombin potential (ETP) increased concentration dependently, reaching near-normal levels at concizumab concentrations >10 nm. Repeated s.c. doses of concizumab in healthy subjects increased both peak thrombin and ETP; these effects were sustained throughout the dosing interval. CONCLUSIONS: Thrombin generation assay demonstrated increased thrombin generation with concizumab after ex vivo spiking of haemophilia plasma and multiple s.c. doses in healthy subjects, supporting both the utility of the TGA in evaluating concizumab treatment and the potential of s.c. concizumab as a novel haemophilia therapy.

Modulation of the activated protein C pathway in severe haemophilia A patients: The effects of thrombomodulin and a factor V-stabilizing fab.

INTRODUCTION: The thrombomodulin (TM)/activated protein C (APC) system is a key regulator of haemostasis, limiting amplification and propagation of the formed blood clot to the injury site. Dampening APC's inhibition of factor V (FV) and factor VIII (FVIII) may be a future strategy in developing next-generation therapeutic targets for haemophilia treatment. AIMS: To determine ex vivo the respective concentration-dependent effects of TM and a FV-stabilizing Fab on the APC regulatory pathway in severe FVIII-deficient blood and plasma. METHODS: Ten severe haemophilia A subjects and one healthy control were enrolled. Blood was spiked with TM (0, 1, 2.5, 5, 10, 20.0 nmol/L) and FV-stabilizing Fab (0, 3, 15, 65, 300 nmol/L). The respective effects were compared to FVIII concentrations of 3- and 10% using rotational thromboelastometry clotting time (CT) and thrombin generation analysis (TGA). RESULTS: With 1 and 2.5 nmol/L TM, 5% FVIII resulted in CT similar to the absence of TM, suggesting it completely reversed the effect of APC. Increasing TM concentrations also reduced peak thrombin generation and ETP. The addition of 300 nmol/L FV-stabilizing Fab returned CT to nearly baseline, but for most subjects was less than the effects of 3- or 10% FVIII. The FV-stabilizing Fab produced similar or greater thrombin generation compared to samples with 3- or 10% FVIII. CONCLUSIONS: The FV-stabilizing Fab resulted in enhanced CT and TGA parameters consistent with FVIII levels of 3- and 10%. Additional studies need to further characterize how modulating the APC pathway may prove beneficial in developing new haemophilia drug targets.

Examiner calibration in caries detection for populations and settings where in vivo calibration is not practical.

AIM: to compare two methods of in vitro examiner calibration in populations and settings where clinical (in vivo) calibration is not practical. METHODS: Study design was cross-sectional and fully-crossed. The units of analysis were 880 tooth surfaces, from ten children ages 3 to 4 years. The study had three data components: (1) Examiner training and calibration using the International Caries Detection and Assessment System (ICDAS) e-Learning programme (2) In vivo community-based visual examination and (3) Intra-oral digital photographs of the same tooth surfaces from the in vivo visual examination. Kappa and weighted kappa scores were used to study reliability estimates. Systematic differences in caries assessments were determined using the Stuart Maxwell test. Data were analysed using STATA 13.1 and SAS 9.2. RESULTS: Weighted kappa scores for the in vivo component ranged from 0.50 to 0.66 and from 0.64-0.74, for inter- and intraexaminer reliability, respectively. Caries lesions detected in vivo were also detected on photographs, albeit with more false positives when using photographs. For example, of 46 tooth surfaces assessed as being sound in the in vivo examination, 22 (48%) of these were assessed as having caries when photographs were used as the diagnostic method. CONCLUSIONS: From this research it appears that good quality photographs alone may be used for training and calibration among challenging populations or settings without adversely affecting data quality.

Single nucleotide variant discovery of highly inbred Leghorn and Fayoumi chicken breeds using pooled whole genome resequencing data reveals insights into phenotype differences.

BACKGROUND: Analyses of sequence variants of two distinct and highly inbred chicken lines allowed characterization of genomic variation that may be associated with phenotypic differences between breeds. These lines were the Leghorn, the major contributing breed to commercial white-egg production lines, and the Fayoumi, representative of an outbred indigenous and robust breed. Unique within- and between-line genetic diversity was used to define the genetic differences of the two breeds through the use of variant discovery and functional annotation. RESULTS: Downstream fixation test (F ST ) analysis and subsequent gene ontology (GO) enrichment analysis elucidated major differences between the two lines. The genes with high F ST values for both breeds were used to identify enriched gene ontology terms. Over-enriched GO annotations were uncovered for functions indicative of breed-related traits of pathogen resistance and reproductive ability for Fayoumi and Leghorn, respectively. CONCLUSIONS: Variant analysis elucidated GO functions indicative of breed-predominant phenotypes related to genomic variation in the lines, showing a possible link between the genetic variants and breed traits.

Epistatic interactions associated with fatty acid concentrations of beef from angus sired beef cattle.

BACKGROUND: Consumers are becoming increasingly conscientious about the nutritional value of their food. Consumption of some fatty acids has been associated with human health traits such as blood pressure and cardiovascular disease. Therefore, it is important to investigate genetic variation in content of fatty acids present in meat. Previously publications reported regions of the cattle genome that are additively associated with variation in fatty acid content. This study evaluated epistatic interactions, which could account for additional genetic variation in fatty acid content. RESULTS: Epistatic interactions for 44 fatty acid traits in a population of Angus beef cattle were evaluated with EpiSNPmpi. False discovery rate (FDR) was controlled at 5 % and was limited to well-represented genotypic combinations. Epistatic interactions were detected for 37 triacylglyceride (TAG), 36 phospholipid (PL) fatty acid traits, and three weight traits. A total of 6,181, 7,168, and 0 significant epistatic interactions (FDR < 0.05, 50-animals per genotype combination) were associated with Triacylglyceride fatty acids, Phospholipid fatty acids, and weight traits respectively and most were additive-by-additive interactions. A large number of interactions occurred in potential regions of regulatory control along the chromosomes where genes related to fatty acid metabolism reside. CONCLUSIONS: Many fatty acids were associated with epistatic interactions. Despite a large number of significant interactions, there are a limited number of genomic locations that harbored these interactions. While larger population sizes are needed to accurately validate and quantify these epistatic interactions, the current findings point towards additional genetic variance that can be accounted for within these fatty acid traits.

Genome-wide methylation profile following prenatal and postnatal dietary omega-3 fatty acid supplementation in pigs.

The objective of this study was to determine how prenatal and postnatal dietary omega-3 fatty acids alter white blood cell (leukocyte) DNA methylation of offspring. Fifteen gilts (n = 5 per treatment) were selected from one of three treatments: (i) control diet throughout gestation, lactation and nursery phase (CON); (ii) algal omega-3 fatty acid supplementation enriched in EPA and DHA (Gromega™ ) fed throughout gestation, lactation and nursery phase (Cn3); or (iii) Gromega™ supplementation maternally, during gestation and lactation only, and control diet during the nursery phase (Mn3). At 11 weeks of age and after 8 weeks of post-weaning nursery feeding, buffy coat genomic DNA was subjected to methyl CpG binding protein sequencing. The methylation enriched profile mapped to 26% of the porcine genome. On chromosome 4, a 27.7-kb differentially methylated region downstream of RUNX1T1 was hypomethylated in the Mn3 and Cn3 groups by 91.6% and 85.0% respectively compared to CON pigs. Conversely, hypermethylation was detected in intergenic regions of chromosomes 4 and 12. Regulatory impact factor and differential hubbing methods were used to identify pathways that were coordinately regulated by methylation due to feeding EPA and DHA during pregnancy. Despite limited ability to detect differential methylation, we describe methods that allow the identification of coordinated epigenetic regulation that could not otherwise be detected from subtle single locus changes in methylation. These data provide evidence of novel epigenetic regulation by maternal and early life supplementation of omega-3 fatty acids that may have implications to growth and inflammatory processes.

Child oral health in migrant families: A cross-sectional study of caries in 1-4 year old children from migrant backgrounds residing in Melbourne, Australia.

UNLABELLED: Early Childhood Caries (ECC) is the most common, preventable disease of childhood. It can affect children's health and wellbeing and children from migrant families may be at greater risk of developing ECC. OBJECTIVE: To describe ECC in children from migrant families, and explore possible influences. BASIC RESEARCH DESIGN: Cross-sectional analysis of caries data collected as baseline data for an oral health promotion study. PARTICIPANTS: The analysis sample included 630 1-4 year-old children clustered within 481 Iraqi, Lebanese and Pakistani families in Melbourne, Australia. METHOD: Child participants received a community-based visual dental examination. Parents completed a self-administered questionnaire on demographics, ethnicity, and oral health knowledge, behaviour and attitudes. MAIN OUTCOME MEASURE: Child caries experience. Bivariate associations between oral health behaviours and ethnicity were tested for significance using chi-square. Multivariate logistic regression analyses were performed to identify associations with ECC, adjusting for demographic variables and accounting for clustering by family. RESULTS: Overall, 34% of children in the sample experienced caries (both non-cavitated and cavitated). For all caries lesions, parent' length of residence in Australia, consumption of sweet drinks and parental education remained as independent predictors of child caries experience. Adding sugar to drinks was an additional risk factor for cavitation. Ethnicity was associated with some individual oral health behaviours suggesting cultural influences on health, however the relationship was not independent of other predictors. CONCLUSION: Culturally competent oral health promotion interventions should aim to support migrant families with young children, and focus on reducing sweet drink consumption.

Choosing foods for infants: a qualitative study of the factors that influence mothers.

BACKGROUND: Examining the experiences of parents making food choices for infants is important because ultimately this influences what infants eat. Infancy is a critical period when food preferences and eating behaviour begin to develop, shaping dietary patterns, growth and health outcomes. There is limited evidence regarding what or why foods are chosen for infants. OBJECTIVE: To describe the experiences of mothers making food choices for their infant children. METHODS: Semi-structured interviews with 32 Australian mothers of infants aged four to 15 months from a range of socioeconomic backgrounds. An inductive thematic analysis through a process of constant comparison was conducted on transcribed interviews. RESULTS: Mothers described many ideas and circumstances which influenced food choices they made for infants. Themes were developed which encapsulate how the wider environment and individual circumstances combine to result in the food choices made for infants. Beliefs, values, norms and knowledge were a central influence on choices. Cost, quality and availabilities of various foods were also key factors. Related to this, and combined with inherent factors such as perishability and infant acceptability, fresh fruits and vegetables were often singled out as an easy or difficult choice. Influences of time, parents' capacities, social connections and different information sources were clearly apparent. Finally infants' own preferences and how parents helped infants with learning to eat were also key influences on food choices. CONCLUSIONS: Choosing foods for infants is a complex social practice. An ecological framework depicting the multiple influences on what people eat and sociological theory on food choice regarding the role of 'social structure' and 'human agency' are both applicable to the process of choosing foods for infants. Equity issues may be key regarding the degree to which mothers can choose particular foods for infants (e.g. choosing foods which promote health).

Transition from milks to the introduction of solid foods across the first 2 years of life: findings from an Australian birth cohort study.

BACKGROUND: The current literature regarding the transition from milks to solid foods across the first 2 years of life is limited despite the important influence of early dietary intake on children's growth and development. The present study describes dietary intake from birth to 2 years across four developmental relevant time-points within an Australian birth cohort. METHODS: Dietary data from 466 infants was collected at four time-points in the first 2 years of life via parent-reported questionnaire, including a 45-item food and beverage frequency questionnaire. Subsample analyses of children who were aged 1-3, 6-8, 12-14 and 18-20 months at the time of data collection were conducted. RESULTS: Infant formula remained consistently consumed by over 75% of children from the 6-8- to 18-20 months old age groups. Mean (SD) age of introduction to solid foods was 5.2 (1.3) months. Almost 20% and 10% of children were introduced before 16 and after 32 weeks, respectively. The highest consumption of core foods, recommended for a healthy diet, daily was seen in the 12-14 months old age group with lower proportions in the 18-20 months old age group coinciding with an increased proportion of children eating discretionary choice foods, not recommended for a healthy diet. Discretionary choice foods/beverages presented in children's diets as early as in the 6-8 months old age group. By 18-20 months, at least 20% of children were consuming savoury biscuits, sweet biscuits, muesli bars and luncheon meats at least twice a week. CONCLUSIONS: The present study identified a number of findings outside the recommendations of the Australian Dietary and Infant Feeding Guidelines. Further work is warranted to explore these outcomes.

The health perspectives of Australian adolescents from same-sex parent families: a mixed methods study.

BACKGROUND: Research involving adolescents from same-sex parent families provides an important contribution to the evidence base on their health, well-being and the impact of stigma. To date reports on the perspectives of adolescents with same-sex attracted parents have been limited. This study aimed to describe the multidimensional experiences of physical, mental and social well-being of adolescents living in this context. METHODS: A mixed methods study of adolescents with same-sex attracted parents comprising of an adolescent-report survey of 10- to 17-year-olds and family interviews with adolescents and their parents. Data were collected in 2012 and 2013 as part of the Australian Study of Child Health in Same-Sex Families. RESULTS: The findings from qualitative interviews with seven adolescents and responses to an open-ended survey question (n = 16) suggest four themes: perceptions of normality, positive concepts of health, spheres of life (including family, friends and community) and avoiding negativity. The quantitative sample of adolescents with same-sex attracted parents (n = 35) reported higher scores than population normative data on the dimensions general health and family activities within the Child Health Questionnaire (CHQ) as well as higher on the peer problems scale on the Strengths and Difficulties Questionnaire (SDQ). Perceived stigma correlates with lower health and well-being overall. CONCLUSIONS: Positive health outcomes are informed by the ways adolescents conceptualize health and how they construct their spheres of life. Peer relationships, and community perspectives of same-sex families, inform perceived stigma and its correlation with poorer health and well-being. Although adolescents see their families as essentially normal they are negatively affected by external societal stigma.

Shifting sands - from descriptions to solutions.

BACKGROUND: Public health practitioners and policymakers value research evidence as one of many resources to use in evidence-informed decision making (EIDM) for public health. However, both researchers and decision-makers have described persistent barriers and facilitators involved in using research evidence for public health practice and policy. This is likely to affect the extent to which research evidence is influential or useful in decisions. Numerous taxonomies, typologies and frameworks are available to guide action in EIDM, but their application in practice is relatively unknown. METHODS: The Public Health Evidence group based in Australia, which incorporates The Cochrane Collaboration's Public Health Review Group, have adapted a number of conceptualizations of research use and types of evidence into a practical typology that defines and illustrates three main types of evidence used in evidence-informed public health: data (Type 1), intervention effectiveness (Type 2) and implementation evidence (Type 3). The authors have actively used this typology within our primary research, evidence synthesis, workforce development and stakeholder engagement strategies, which has enabled practical application of these concepts. To test the relevance of the typology in practice, relevant findings from our applied research and evaluation (including two exploratory studies of evidence use in decision-making and evaluations of the use and impact of systematic reviews among end-users) were triangulated. RESULTS: The typology has been useful in stakeholder interactions when defining evidence, and identifying processes for EIDM. There was a preference for defining evidence as descriptive evidence (data) rather than impact evidence and implementation evidence. Practitioners were confident and competent at generating and using data and community views descriptively for priority setting (describing the problem). However, finding and using impact and implementation evidence appropriate for strategy development (effective solutions) was often described as a more daunting task. As a result, there was low awareness of, and competence with, Types 2 and 3 evidence. Organizational processes for using these types of evidence were almost non-existent. DISCUSSION: Applying this typology with stakeholders has allowed us to observe that it; (1) has been useful in conceptualizing useful evidence for public health, which has guided our work (2) has been useful in stakeholder interactions to introduce evidence, its definition and what it means to be 'evidence-informed' and (3) has identified 'faults' in the EIDM approach. The typology includes examples of common questions in public health, and suggestions of the types of evidence that may be useful to answer those questions. Findings that test the use of the typology have been synthesized. These have demonstrated inconsistencies in defining and applying evidence, and low awareness about what types of evidence are crucial to ensure that interventions are effective and minimize harm. Based upon these findings, the authors would argue that current investment in type 1 evidence (e.g. data repositories) shifts to make way for KT strategies, which facilitate the uptake of type 2 and 3 evidence (interventions and implementation guidance). CONCLUSIONS: Building a shared understanding of the types of evidence and their importance in public health decision-making is crucial if we wish to build a system that supports EIDM and results in effective interventions being delivered. There are a number of 'faults' in the system which the authors have illuminated through understanding the individual and organizational realities of evidence use. These faults could be addressed through KT strategies with the public health workforce, and development of organizational cultures and the broader system.

Morbidity patterns among the underweight, overweight and obese between 2 and 18 years: population-based cross-sectional analyses.

CONTEXT: No study has documented how symptomatic morbidity varies across the body mass index (BMI) spectrum (underweight, normal weight, overweight and obese) or across the entire child and adolescent age range. OBJECTIVE: To (1) quantify physical and psychosocial morbidities experienced by 2-18-year-olds according to BMI status and (2) explore morbidity patterns by age. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional data from two Australian population studies (the Longitudinal Study of Australian Children and the Health of Young Victorians Study) were collected during 2000-2006. Participants were grouped into five age bands: 2-3 (n=4606), 4-5 (n=4983), 6-7 (n=4464), 8-12 (n=1541) and 13-18 (n=928) years. MAIN MEASURES: Outcomes-Parent- and self-reported global health; physical, psychosocial and mental health; special health-care needs; wheeze; asthma and sleep problems. Exposure-measured BMI (kg m(-2)) categorised using standard international cutpoints. ANALYSES: The variation in comorbidities across BMI categories within and between age bands was examined using linear and logistic regression models. RESULTS: Comorbidities varied with BMI category for all except sleep problems, generally showing the highest levels for the obese category. However, patterns differed markedly between age groups. In particular, poorer global health and special health-care needs were associated with underweight in young children, but obesity in older children. Prevalence of poorer physical health varied little by BMI in 2-5-year-olds, but from 6 to 7 years was increasingly associated with obesity. Normal-weight children tended to experience the best psychosocial and mental health, with little evidence that the U-shaped associations of these variables with BMI status varied by age. Wheeze and asthma increased slightly with BMI at all ages. CONCLUSIONS: Deviation from normal weight is associated with health differences in children and adolescents that vary by morbidity and age. As well as lowering risks for later disease, promoting normal body weight appears central to improving the health and well-being of the young.

Methodology for the evaluation of the Stephanie Alexander Kitchen Garden program.

ISSUES ADDRESSED: Community and school cooking and gardening programs have recently increased internationally. However, despite promising indications, there is limited evidence of their effectiveness. This paper presents the evaluation framework and methods negotiated and developed to meet the information needs of all stakeholders for the Stephanie Alexander Kitchen Garden (SAKG) program, a combined cooking and gardening program implemented in selectively funded primary schools across Australia. METHODS: The evaluation used multiple aligned theoretical frameworks and models, including a public health ecological approach, principles of effective health promotion and models of experiential learning. The evaluation is a non-randomised comparison of six schools receiving the program (intervention) and six comparison schools (all government-funded primary schools) in urban and rural areas of Victoria, Australia. A mixed-methods approach was used, relying on qualitative measures to understand changes in school cultures and the experiential impacts on children, families, teachers, parents and volunteers, and quantitative measures at baseline and 1 year follow up to provide supporting information regarding patterns of change. RESULTS: The evaluation study design addressed the limitations of many existing evaluation studies of cooking or garden programs. The multistrand approach to the mixed methodology maintained the rigour of the respective methods and provided an opportunity to explore complexity in the findings. Limited sensitivity of some of the quantitative measures was identified, as well as the potential for bias in the coding of the open-ended questions. CONCLUSION: The SAKG evaluation methodology will address the need for appropriate evaluation approaches for school-based kitchen garden programs. It demonstrates the feasibility of a meaningful, comprehensive evaluation of school-based programs and also demonstrates the central role qualitative methods can have in a mixed-method evaluation. So what? This paper contributes to debate about appropriate evaluation approaches to meet the information needs of all stakeholders and will support the sharing of measures and potential comparisons between program outcomes for comparable population groups and settings.

Open thoracic surgical implantation of cardiac pacemakers in rats.

Genetic engineering and implantable bioelectronics have transformed investigations of cardiovascular physiology and disease. However, the two approaches have been difficult to combine in the same species: genetic engineering is applied primarily in rodents, and implantable devices generally require larger animal models. We recently developed several miniature cardiac bioelectronic devices suitable for mice and rats to enable the advantages of molecular tools and implantable devices to be combined. Successful implementation of these device-enabled studies requires microsurgery approaches that reliably interface bioelectronics to the beating heart with minimal disruption to native physiology. Here we describe how to perform an open thoracic surgical technique for epicardial implantation of wireless cardiac pacemakers in adult rats that has lower mortality than transvenous implantation approaches. In addition, we provide the methodology for a full biocompatibility assessment of the physiological response to the implanted device. The surgical implantation procedure takes ~40 min for operators experienced in microsurgery to complete, and six to eight surgeries can be completed in 1 d. Implanted pacemakers provide programmed electrical stimulation for over 1 month. This protocol has broad applications to harness implantable bioelectronics to enable fully conscious in vivo studies of cardiovascular physiology in transgenic rodent disease models.

Parent proxy-reported quality of life for children with cerebral palsy: is it related to parental psychosocial distress?

BACKGROUND: Parent-proxy reports of quality of life (QOL) are often used to guide decisions about children with cerebral palsy (CP), although little is known about the factors that influence parent-proxy reports. The aim of this study was to examine (i) the relationship between parental psychosocial distress and parent proxy-reported QOL; and (ii) whether parental psychosocial distress mediates the relationship between child impairment and proxy-reported QOL. METHODS: A sample of 201 primary caregivers of children aged 4-12 years with CP completed the Cerebral Palsy Quality of Life Questionnaire for Children, a condition-specific QOL instrument, and a measure of psychosocial distress, the Kessler 10. The children, evenly distributed by gender (56% male) were sampled across Gross Motor Function Classification System levels (Level I = 18%, II = 28%, III = 14%, IV = 11%, V = 27%). RESULTS: Consistent with the hypotheses, parental distress was negatively correlated with all domains of parent proxy-reported QOL (r = -0.18 to r = -0.55). The relationship between impairment and proxy-reported QOL was mediated by parental distress for five of the seven domains of QOL (social well-being and acceptance, feelings about functioning, participation and physical health, emotional well-being and self-esteem, and pain and impact of disability). Child impairment did not predict access to services or family health. CONCLUSION: This is the first study that assesses the relationship between parental distress and proxy-reported QOL for children with CP. Although the cross-sectional nature of the available data precludes any statements of causality, the results suggest that, when using parent proxy, the parents' psychological state should also be measured. This is particularly important when, as is often the case for child disability research, proxy-reported QOL are the only available data.

Aggregation and competitive exclusion: explaining the coexistence of human Papillomavirus types and the effectiveness of limited vaccine conferred cross-immunity.

Human Papillomavirus (HPV) types are sexually transmitted infections that cause a number of human cancers. According to the competitive exclusion principle in ecology, HPV types that have lower transmission probabilities and shorter durations of infection should be outcompeted by more virulent types. This, however, is not the case, as numerous HPV types co-exist, some which are less transmissible and more easily cleared than others. This paper examines whether this exception to the competitive exclusion principle can be explained by the aggregation of infection with HPV types, which results in patchy spatial distributions of infection, and what implications this has for the effect of vaccination on multiple HPV types. A deterministic transmission model is presented that models the patchy distribution of infected individuals using Lloyd's mean crowding. It is first shown that higher aggregation can result in a reduced capacity for onward transmission and reduce the required efficacy of vaccination. It is shown that greater patchiness in the distribution of lower prevalence HPV types permits co-existence. This affirms the hypothesis that the aggregation of HPV types provides an explanation for the violation of the competitive exclusion principle. Greater aggregation of lower prevalence types has important implications where type-specific HPV vaccines also offer cross-protection against non-target types. It is demonstrated that the degree of cross-protection can be less than the degree of vaccine protection conferred against directly targeted types and still result in the elimination of non-target types when these non-target types are patchily distributed.